Influenza Vaccine Innovation

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United States Department of Health & Human Services Office of the

Innovation New Vaccines Approved and on the Way Rick A. Bright, Ph.D.

Development Authority (BARDA) 2013 National Adult and Influenza

Advanced Research and Development Authority Develop and provide

infectious diseases through product development, stockpile

1 United States Department of Health & Human Services Office of the Assistant Secretary for Preparedness and Response Influenza Vaccine Innovation New Vaccines Approved and on the Way Rick A. Bright, Ph.D. Deputy Director, Influenza Division Biomedical Advanced Research and Development Authority (BARDA) 2013 National Adult and Influenza Immunization Summit May 14 16, 2013 Atlanta, GA USA The Biomedical Advanced Research and Development Authority Develop and provide countermeasures for CBRN threats, pandemic influenza, and emerging infectious diseases through product development, stockpile acquisition/building, manufacturing infrastructure building, and product innovation. Vaccines Therapeutics Diagnostics Devices Infrastructure 2 1

Requirements Requirements addressed by the BARDA

documents that guide the US Government efforts to

Pandemic Influenza (Nov 2005) HHS Pandemic

Pandemic Influenza Implementation Plan (May 2006)

Review (Aug 2010) PCAST report on Reengineering

2010) 3 Vaccine Challenges Pandemic Response

" The 2009 H1N1 Influenza Vaccination Campaign:

2 Requirements Requirements addressed by the BARDA Influenza Portfolio are derived from a number of documents that guide the US Government efforts to prepare for pandemics National Strategy for Pandemic Influenza (Nov 2005) HHS Pandemic Influenza Plan (Nov 2005) Nation Strategy for Pandemic Influenza Implementation Plan (May 2006) Public Health Emergency Medical Countermeasures Review (Aug 2010) PCAST report on Reengineering the Influenza Vaccine Production Enterprise (Aug 2010) 3 Vaccine Challenges Pandemic Response National Research Council, "Vaccine Supply." The 2009 H1N1 Influenza Vaccination Campaign: Summary of a Workshop Series. Washington, DC: The National Academies Press,

3 PRODUCT PIPELINE Vaccine Challenges The Development Process TIME COST PER PHASE PHASE TRLs 3-7 yr yr 1-2 yr yr yr 1-2 yrs $100M -130M $60-70M $70M-100M $130M-160M $190M-220M $18M-20M IND NDA/BLA Discovery Preclinical Development Phase I Phase II Phase III Licensure Production & Delivery Licensed Product 1-3% 5-17% 10-25% 18-35% 45-70% 90% PROBABILITY OF SUCCESS TO LICENSURE 5 candidates here yield 1 product here Sources: PRTM & Industry Data 5 Vaccine Challenges Financial Outlook Pre-2004 NGO VC NGO Post-2009 VC NGO VC INDUSTRY GOV T INDUSTRY GOV T INDUSTRY GOV T Approximate scale of total investments: ~$100M ~$10B ~$1B Trends Budget austerity across all levels of government Industry economic pressures towards reliable opportunities and faster return on investment Smaller amounts of available venture capital funding 6 3

4 Institutul Cantacuzino SERUM INSTITUTE OF INDIA LTD Influenza Vaccine Landscape Egg-based inactivated Pre Clinical Phase 1 Phase 2 Phase 3 Market Approval WIV Egg inactivated Fill/Finish sp Split H5N1 WIV +Alum Flu intradermal; H5N1 WIV w/ Adjuvant Proteosome intranasal improved seasonal H5N1 Surface antigen w/ AlPO 4 Split WIV Split WIV Fil / Finish Egg, Thailand Split H9N2 virosomal & whole H5N1, WIV sp H5N1 + GSK AS03 H5N1 AS03 QIV Adimmune- Taiwan Seasonal Split HuaLan Pandemic Seasonal Seasonal WIV Seasonal Split Cell-culture inactivated H5N1 EB 66 Cells H9N2 virosomal & whole Monkey Kidney Cell MDCK subunit (EU) US 2009/2010 Vero, Influject/ Cevapan(EU) H1N1 Cell; HN-VAC (India) LAIV Egg, Thailand MDCK H5N1 dns1 - Vero Egg H5N1/H9N2 Egg, H5N2 SIIL Egg Egg QIV Serum Institute of India Ltd Egg Egg (Russia) Recombinant (VLPs) dns1- Vero H5 Egg, Thailand H1 Egg, Thailand VLP / HA VLP, Insect cells VLP, 293 cells rha, Plants rha Insect cells VLP, Plants VLP, Insect Cells rha, Insect cells Salmonella, Oral VLP, Fungus Yeast, IN - Oral HA, Flagellin, e coli Salmonella, Oral Chimeric VLP + microneedles VLP, insect cells rha Insect Cells Seasonal Universal Vectors/ Adjuvant Molecular HAs rha, Plants rha, Plants NYU / MSSM SynBio LAIV HA stalk COBRA HA VLP Egg inactivated NP & ISS Tech Peptide based M2e M2e Liposome Novel peptides MVA Based Adenovirus M & NP Adenovirus Adenovirus, Oral Split MVA Mass Gen Hospital MVA Based Listeria Seasonal DNA 7 M2e flagellin Pandemic Seasonal & Pandemic US License Dormant DNA / SnyCon w/ DNA / Vaxfectin Electroporation Updated: 6MAR2013 Current Influenza Vaccines Safe and efficacious, decades of experience Vulnerable to antigenic drifts and shifts Antibodies target highly variable regions of HA and NA Protection following vaccination or infection is limited to specific strains Single site mutations can reduce efficacy Host variations in immune response can reduce efficacy Non-adjuvanted vaccines provide minimal crossprotection within subtypes or against other subtypes Short duration of immunity, particularly in at-risk populations (e.g., pediatric, geriatric) 8 4

5 10 Ideal Attributes of Next-Generation Vaccines Effective in general and at-risk populations Broadly reactive against multiple strains Low cost per dose Safe for use in all populations Rapid, scalable production Long-lasting immunity 9 More BARDA s Approach to Vaccine Innovation Maximizing vaccine supply Faster Minimizing the timeframe from pandemic virus identification to first vaccine dose Better Driving generational improvements in manufacturability, speed, and effectiveness 5

11 12 Maximizing Near-Term Technologies Egg-based vaccines Contracts to ensure year-round egg supply Licensure of first H5N1 vaccine Adjuvanted vaccines Cell-based vaccines Advanced

6 11 12 Maximizing Near-Term Technologies Egg-based vaccines Contracts to ensure year-round egg supply Licensure of first H5N1 vaccine Adjuvanted vaccines Cell-based vaccines Advanced development of multiple technologies Establish infrastructure for U.S.-based manufacturing International vaccine programs First U.S. Cell-Based Facility Landmark Public-Private Partnership 6

7 Global Influenza Vaccine Production circa 2006 Licensed Influenza Vaccine Producers 13 Global Influenza Vaccine Production circa 2012 Romania Cantacuzino Institute Kazakhstan RIBSP Serbia Torlak Institute South Korea Green Cross Mexico Birmex Egypt VACSERA India Serum Institute Thailand GPO Vietnam IVAC VABIOTECH PATH Brazil Instituto Butantan South Africa Biovac Indonesia Bio Farma Licensed/Active Influenza Vaccine Producers BARDA/WHO Cooperative Agreement Grantees 14 7

15 More BARDA s Approach to Vaccine Innovation Maximizing vaccine supply Faster Minimizing the timeframe from pandemic virus identification to first vaccine dose Better Driving generational

8 15 More BARDA s Approach to Vaccine Innovation Maximizing vaccine supply Faster Minimizing the timeframe from pandemic virus identification to first vaccine dose Better Driving generational improvements in manufacturability, speed, and effectiveness Influenza Vaccine Virus Selection and Development Process

9 Traditional Egg-based Vaccine Manufacturing Processes Virus Isolate & Re-assort Testing Egg Based Amplify Egg Production Filling Distribution Packaging 17 Influenza Vaccine Manufacturing Improvement Initiative Novel set of optimized donor viruses WT Reassortment 17 days Seed Faster sterility assays Reagent calibration and potency assays 9

x x x x x Synthetic Biology Vaccine Seed Production Rapid synthesis process to assemble oligos into flu HA and NA segments in <1 day x Pool overlapping oligos for HA or NA

5 hr 3.0 hr 1.0 hr Amplify to get linear synthetic HA or NA segments Precipitate DNA and clean up reactions 2.0 hr 1.0 hr Final product is uncloned, synthetic linear HA or NA gene segment with regulatory control elements (promoters & terminators).

Influenza Vaccine Seeds FFA Synthetic Biology Vaccine Seed Production Robust process to rescue influenza virus using synthetic gene segments in vaccine-approved MDCK cells **

in infected cells IVMI Program Workshop Dormitzer August 28, 2012 Synthetic Influenza Vaccine Seeds Seed MDCK cells Transfect cells with DNA Remove serum, add feeder cells and

10 x x x x x Synthetic Biology Vaccine Seed Production Rapid synthesis process to assemble oligos into flu HA and NA segments in <1 day x Pool overlapping oligos for HA or NA Assemble and amplify oligos Error-correct & reamplify Assemble oligos into linearized pks10 vector to add essential reverse genetics promoter and terminator elements 0.5 hr 2.5 hr 3.0 hr 1.0 hr Amplify to get linear synthetic HA or NA segments Precipitate DNA and clean up reactions 2.0 hr 1.0 hr Final product is uncloned, synthetic linear HA or NA gene segment with regulatory control elements (promoters & terminators). Total = hours ASPR: IVMI Resilient Program Workshop People. Healthy Dormitzer Communities. August 28, 2012 A Nation Synthetic Prepared. Influenza Vaccine Seeds FFA Synthetic Biology Vaccine Seed Production Robust process to rescue influenza virus using synthetic gene segments in vaccine-approved MDCK cells ** focus-formation assay; based on immunological ASPR: Resilient People. Healthy staining Communities. of viral nucleoprotein A Nation Prepared. in infected cells IVMI Program Workshop Dormitzer August 28, 2012 Synthetic Influenza Vaccine Seeds Seed MDCK cells Transfect cells with DNA Remove serum, add feeder cells and trypsin * Monitor virus rescue daily by FFA** Confirmed viruses = 4-7 days * Replenish trypsin concentration every 48h if rescues take longer than 3 days. Day 0 Day 1 Day 2 Days

21 More BARDA s Approach to Vaccine Innovation Maximizing vaccine

identification to first vaccine dose Better Driving generational

Recombinant Vaccine Production Recombinant technologies provide

11 21 More BARDA s Approach to Vaccine Innovation Maximizing vaccine supply Faster Minimizing the timeframe from pandemic virus identification to first vaccine dose Better Driving generational improvements in manufacturability, speed, and effectiveness Recombinant Vaccine Production Recombinant technologies provide vaccine sooner with less dependence on influenza virus strain properties 22 11

Distribution Packaging 23 Other Novel Approaches DNA vaccines Live-viral vectors (adenovirus, modified

12 New Vaccine Production Paradigm Virus Sequence or Isolate & Re-assort Synthetic Seed Expression Vector Testing Cell Based Egg Based Recombinant Production Amplify Egg Production Filling Cell Production Distribution Packaging 23 Other Novel Approaches DNA vaccines Live-viral vectors (adenovirus, modified vaccinia) Other expression systems (E. coli, Neurospora) Synthetic vaccinology from sequence to vaccine 24 12

13 The Influenza Crystal Ball Adapted from: Paul Lewis, MD Oregon State Public Health 25 Universal Influenza Vaccine Many definitions for a universal influenza vaccine A single influenza vaccine that would provide protection against any given subtype of influenza A and/or B Could be used for several influenza seasons before reformulation Reduce annual guesswork for strain selection Reduce production costs (thus vaccine costs/year round production) Reduce vaccine mismatches Reduce the potential for vaccine shortages Increase the global supply of vaccine Could be stockpiled for epidemics/pandemics Surge capacity Rapid scale-up, reduce production bottlenecks 26 13

Universal Vaccine Strategies Leveraging Old and

epitopes (HA Stalk, M2 extracellular, NP)

Target occluded sites Vaccine Design Adjuvants

Universal Vaccines No universal definition or

need to evolve with the technical science

to something other than the HA protein (non-hai)

identified Alternate potency/release assays will

14 Universal Vaccine Strategies Leveraging Old and New Discoveries Identify broadly reactive epitopes (HA Stalk, M2 extracellular, NP) Multi-epitope vaccines Vector delivered vaccine Target occluded sites Vaccine Design Adjuvants Broaden B cell epitope recognition Th1 vs Th2 responses Humoral vs Cell-mediated Administration HA1 (variable region) HA2 (conserved region) R. Rappuoli, F1000 Medicine Reports 3 (2011): 16. Location: Intranasal, intradermal or intramuscular Timing: Prime/boost Regimen Source: NIAID 27 Developmental Challenges for Universal Vaccines No universal definition or target product profile Regulatory science will need to evolve with the technical science development Protective immune responses may be to something other than the HA protein (non-hai) New surrogates of immunity may need to be identified Alternate potency/release assays will be needed Large scale efficacy trials or other creative clinical development approaches may be required Funding is limited Most candidates are in preclinical development stage 28 14

15 National Pandemic Influenza Vaccine Development Strategy: Multi-Step & Integrated Approach More and better vaccines sooner Universal Vaccines Recombinant-based Vaccines Cell-based Vaccines Flublok Licensed 01/16/13 Egg-based Vaccines Flucelvax Licensed 11/20/12 29 Final Thoughts The landscape of new influenza vaccine development is active and rapidly evolving Significant technical challenges for innovative technologies Continued scientific discoveries provide greater opportunities for innovation Post-pandemic fatigue and economic challenges affect all partners Leveraging government, nonprofit and industry collaborations will be essential to continued public health success 30 15

Assessment of Influenza Vaccine Production Compatibilities

United States Department of Health & Human Services Office of the Assistant Secretary for Preparedness and Response Assessment of Influenza Vaccine Production Compatibilities Joshua Speidel, PhD Influenza